The long term goal of this application is to advance our knowledge of inherited human hemorrhagic diseases through the study of appropriate and genetically defined mouse models. A related goal is to utilize mouse mutants to further understand the regulation of the biosynthesis and processing of subcellular organelles. This characterization is expected to lead to an understanding of the basic cell biology of complex hemorrhagic processes and ultimately to beneficial gene therapy in cases of severe forms of hemorrhagic diseases. The first specific aim is to identify molecular markers near 5 genes which cause hemorrhagic disease in specific mouse mutants. Four mutants, including the ruby-eye and pale ear pigment genes on chromosome 19 and the pearl and muted genes on chromosome 13, are animal models of platelet storage pool deficiency (SPD) and in particular are models for the Hermansky-Pudlak Syndrome (HPS) form of SPD. The 5th mutant, brachymorphic, is a possible animal model for human Thrombocytopenia with Absent Radii (TAR) syndrome. This aim represents an intermediate step toward the long term goal of the cloning and characterization of the hemorrhagic genes per se. The methods for accomplishing this aim include the use of interspecific mouse crosses in which the parental strains are highly polymorphic for almost all genes. Polymorphic forms of molecular probes will be defined by Southern blotting and/or polymerase chain reaction technology. The second aim is to map the genes which cause Type 1A von Willebrand Disease (vWD) and a deficiency of Factor XI in the RIIIS/J inbred mouse strain. Type 1A is the most common form of vWD in humans. Preliminary experiments suggest the interesting possibility that the RIIIS/J vWD disease is caused by an altered regulatory gene rather than an altered form of the von Willebrand Factor (vWF) structural gene. The methods will include the use of backcrosses of RIIIS/J and wild-derived mice to follow the segregation of vWF and Factor XI genes. The third specific aim is to identify and partially characterize new mouse models of human hemorrhagic diseases. Thus far, 5 new mutants with novel characteristics have been found. These and other mouse mutants will be characterized by a battery of hematological and cell biological tests.